A diagnosis of PEComa is made on the basis of histological and immunohistochemical findings. Basic characteristic features of perivascular epithelioid cells include abundant clear to eosinophilic granular cytoplasm with an immunoprofile of HMB45 positivity and lack of expression of S-100 protein, though the latter is positive in a minority of cases. Other features include expression of another melanoma-associated antigen melan A, coexpression of muscle cell markers without cytokeratin expression and the presence of melanosomes or pre-melanosomes. In this case the tumor cells expressed HMB45, melan A and smooth muscle actin.
PEComas of the gynecological tract account for approximately 40% of reported cases . In the pelvis, the uterine body appears to be the most prominent site of this rare tumor, with smaller numbers of PEComas reported in the broad ligament, pelvic soft tissue, cervix, vagina and the urinary bladder [4–7].
Morphologically there are two types, epithelioid and spindle cell. In the epithelioid type the cells have clear to lightly eosinophilic, finely granular cytoplasm and may form thick-walled pseudo blood vessels. The spindle cell type, which has fascicles and nests of spindle cells with clear to lightly eosinophilic cytoplasm arrayed around an elaborate capillary sized vascular network, forms the majority of cases .
Uterine PEComas are characterized by perivascular epithelioid cells that are HMB45 positive/S-100 protein negative with abundant clear to eosinophilic granular cytoplasm, but there may be an overlap with some epithelioid smooth muscle tumors of the uterus making the initial diagnosis difficult . The patient's lesion is epithelioid in nature. Other differential diagnoses that should be excluded in uterine lesions are endometrial stromal sarcoma and paraganglioma .
The patient had a broad ligament PEComa, of which we were able to identify six other reported cases on a literature search of English language articles performed using the search words of 'broad ligament' and 'PEComa' in January 2011 [3, 7, 9–12]. The age at presentation in these reports ranged from 12 to 51 years. Reported clinical presentation varied from incidental finding of abdominal mass, lower abdominal pain and/or leg pain to abnormal uterine bleeding in a young woman. The tumor typically achieves a large size by the time of diagnosis, representing the difficulty of clinically recognizing these tumors, as was seen in our patient's case.
The current classification of PEComas is based on the morphology and the location of the tumor but this is not an indicator of prognostic outcome. To overcome this, Folpe et al. have proposed criteria for classification of these tumors into three groups: benign, of uncertain malignant potential and malignant, based on tumor size, level of infiltration, nuclear grade, cellularity, mitotic rate, necrosis and vascular invasion . Using these criteria, the patient's histology and immunohistochemistry (as detailed above) favor the lesion being classified as a malignant PEComa, and although the tumor has not metastasized, it has behaved in a locally malignant fashion. However, long-term follow-up of a larger number of patients will be required prior to the proposed classification being used as a prognostic indicator.
Duration of follow-up in the literature has varied from eight to 18 months; it is now 47 months since this patient's TAH BSO with persistent evidence of tumor following an initial diagnosis of malignant PEComa.
Reported management mainly includes surgical excision, but this ranged from removal of mass, salpingo-oophorectomy to total abdominal hysterectomy and bilateral salpingo-oophorectomy. In addition, one patient had pelvic radiation along with the TAH BSO and another required re-excision, though local recurrence occurred in three out of six patients [3, 11, 12]. Our patient underwent initial TAH BSO, followed by USS-guided (ultrasound scan) aspiration of hematoma, pelvic radiation and a trial of sirolimus, which has resulted in some tumor shrinkage that has continued. She has remained symptomatic throughout, mainly from pelvic pain.
Sirolimus is an immunosuppressive agent approved by the US Food and Drug administration for use in the management of renal transplant, renal cell carcinoma and acute myeloid leukemia [13, 14]. It inhibits the activation and proliferation of T lymphocytes in response to stimulation by antigens and cytokines (interleukin (IL)-2, IL-4, and IL-15) while also inhibiting antibody production. At a cellular level, it inhibits the activation of the mammalian target of rapamycin (mTOR), a key regulatory kinase, leading to suppression of cytokine-driven T cell proliferation and inhibition of cell cycle from the G1 to the S phase. Sirolimus (rapamycin) is of course the archetypal inhibitor of mTOR, which in cancer cells is associated with increased angiogenesis, stimulation of protein synthesis and inhibition of cell death. PEComas are associated with mutations or deletions of tuberous sclerosis associated genes TSC1 or TSC2, which act as tumor suppressor genes by regulating mTOR. Their loss results in upregulation of the mTOR pathway. An encouraging recent case series of three patients with advanced malignant PEComa treated with sirolimus reported radiological response and disease stabilization . There was evidence in archive material of changes in TSC1 or TSC2 in these tumors but these findings were inconsistent and indicate the need for further investigation of the mechanism of mTOR activation in these diseases .
Italiano et al. also reported a series of two patients with malignant metastatic uterine PEComas, one treated successfully with the mTOR inhibitor temsirolimus (now disease free following resection of her pulmonary metastasis) and the other showing a partial response followed by disease progression, with the temsirolimus being stopped at 22 weeks because of this .
Subbiah et al. subsequently reported a case of a 58-year-old woman who underwent surgical resection of a malignant PEComa arising from the retroperitoneum above the right kidney. She subsequently developed hepatic metastases whilst on doxorubicin chemotherapy. Following radiotherapy and further chemotherapy, she was treated with temsirolimus but her disease continued to progress and at the time of reporting, she had elected to undergo palliative care .
A radiological response to sirolimus was seen in our patient with epithelioid PEComa, as demonstrated by the MRI images shown in Figures 1 and 2.